—  SYMPOSIUM #33  —

New Perspectives in Inflammatory Bowel Disease
Moderators: Dr. Stanley Hamilton and Dr. Carolyn C. Compton

Section 4 - What Histological Analysis of Pouches and Diverted Bowel Can and Cannot Do

Neil A Shepherd
Gloucester, UK


Introduction
There are three principle issues to consider when assessing an inflammatory condition of the intestines pathologically. These are context, context and context. This is especially so when the intestines have been subjected to surgery. That surgery creates a new milieu in which adaptive and/or inflammatory changes provide confounding and confusing histological appearances (Warren & Shepherd, 2000). For, d espite its relative heterogeneity, the intestinal mucosa has a limited repertoire of response to changing environments and injurious agents: similar histological appearances can be produced by any number of aetiopathogenetic agents, demanding exact clinical, radiological and endoscopic correlation to attain the correct diagnosis. Both ileal pouches and diverted colorectum are associated with inflammatory changes in the mucosa of the intestine that are prone to misinterpretation by pathologists: this may have major implications for the management of individual patients. This treatise will consider five of the important areas where histological assessment may provide information of fundamental importance for the further management of the patient but may yet provide confusing and contradictory information.

1. Does pouch histology aid in the differentiation of the inflammatory diseases that affect it?
Restorative proctocolectomy with ileal reservoir, known as ileal pouch-anal anastomosis in North America , has become a leading surgical procedure for patients with ulcerative colitis and familial adenomatous polyposis (FAP) requiring total colectomy. Pouch creation has provided pathologists with a whole new field of study. Not unsurprisingly, the pouch acts as a neorectum and morphological changes familiar to pathologists in the rectum also affect the reservoir (Warren & Shepherd, 1993; Yantiss & Odze, 2006). Once the reservoir is established, it shows a form of mucosal adaptation (Shepherd et al 1987; de Silva et al 1991; Setti Carraro et al 1994; Veress et al, 1995). Varying degrees of chronic inflammation and architectural abnormality (villous flattening or partial villous atrophy) are found in almost all (>90%) established pelvic ileal reservoirs (Shepherd et al, 1987). When villous atrophy is severe, there is crypt hyperplasia although there is a lack of the intraepithelial lymphocytic infiltrate that characterises coeliac disease (Shepherd et al, 1987; de Silva et al, 1991). These changes are almost universal: they are much more pronounced in ulcerative colitis patients than those with FAP (Shepherd et al, 1987). It is very important not to equate such common inflammatory changes with a diagnosis of pouchitis.

The adaptive changes have been designated colonic phenotypic change (Shepherd et al, 1993) since the villous atrophy and crypt hyperplasia produces an appearance resembling colon. This may be due to changed faecal flora, although some have suggested the changes are not necessarily adaptive but are, instead, the direct result of inflammation (Fruin et al, 2003). The concept of colonic phenotypic change is supported by studies of mucin and lectin histochemistry, immunohistochemistry, mucin biochemistry and electron microscopy (Warren & Shepherd, 2000). Pouches retain some properties of small bowel mucosa, for instance disaccharidase activity (de Silva et al 1991). Because of this, the term colonic phenotypic change is preferred to colonic metaplasia.

Studies have classified these adaptive changes, in ulcerative colitis patients, into three groups and it appears that the amount of inflammatory/adaptive change is remarkably consistent both within individuals and with time (Setti Carraro et al 1994, 1998; Veress et al 1995). Firstly about 50% of UC patients maintain a relatively healthy reservoir mucosa throughout the life of the pouch with minor villous changes, modest chronic inflammation and minimal active inflammation. A second group comprising about 40% of patients shows intermittent inflammatory changes with reasonable architectural recovery. The third group comprising between 10-20% of the total UC patient group have a flat and chronically inflamed mucosa between acute exacerbations of active inflammation (Setti Carraro et al 1994, 1998; Veress et al 1995). Biopsies taken within the first 6 months of reservoir construction will determine which of the three groups an individual patient falls into and this should therefore give a useful guide to those patients who demand the most rigorous surveillance (Setti Carraro et al, 1994).

Patients who inadvertently undergo pouch surgery for Crohn's disease are at risk of developing the changes of Crohn's disease in their reservoir (Lucarotti et al, 1995). Histologically these changes will resemble Crohn's disease elsewhere in the gut. Nevertheless care is required because any of the individual histological features of Crohn's disease may be seen in the reservoir in patients who do not have Crohn's disease. For instance granulomas are a characteristic feature of reservoir mucosa, usually seen in the centre of lymphoid follicles, both associated with and without pouchitis (Shepherd, 1990). It must be emphasised, however, that the only detailed study of granulomas in the pouch has concluded that they still remain highly predictive for a diagnosis of Crohn's disease (MacNeill et al, 2004). Granulomas may also be seen in the mucosa as a result of ruptured crypts and deep within the wall in relation to suture material (Warren & Shepherd, 1993). Vertical fissures resembling those of Crohn's disease may also be seen in pouch mucosa in relation to ruptured deep crypt abscesses and at anastomosis lines, a feature also seen in the defunctioned rectum in ulcerative colitis (Warren et al, 1993). Fistulae may occur soon after reservoir construction, particularly at suture lines. Crohn's-like complications of the pelvic ileal reservoir may also include anal strictures, perianal abscesses and colovaginal fistulae: all of these may occur in patients with an unequivocal pre-operative diagnosis of ulcerative colitis (Goldstein et al, 1997). This author firmly believes that the diagnosis of Crohn's disease should never be made on the histological appearances seen in the reservoir alone. A change in diagnosis at this stage has grave consequences for the patient and should always be substantiated by examination of the original proctocolectomy specimen or by further examination and investigation of the remaining alimentary tract (Warren & Shepherd, 1993; Goldstein et al, 1997). Context, as ever, remains king.

This treatise cannot hope to cover all pathological entities seen in the pelvic pouch. Important amongst these are mucosal ischaemia, mucosal prolapse, secondary pouchitis, pre-pouch ileitis and cuffitis. The interested reader is referred to other reviews for discussion of these (Warren & Shepherd, 1993 & 2000)

2. Is pouch mucosal histology useful in determining the cause of pouchitis and in its prediction, diagnosis and management?
Pouchitis is the commonest and most important complication of restorative proctocolectomy (Mortensen & Madden, 1993; Sandborn & Pardi, 2004). It remains the most enigmatic condition in terms of pathogenesis, management and prognosis. Many of the uncertainties concerning this disease are because of poor understanding of 'normality' and a lack of uniform criteria for the diagnosis of pouchitis (Warren & Shepherd, 1993; Sandborn & Pardi, 2004). Indeed the term itself, despite its widespread usage, is a poor one that is open to misinterpretation. In the past the term pouchitis has been too loosely applied: many different inflammatory diseases cause active inflammation in the reservoir and have been called pouchitis. The term should be restricted to those patients with an acute-on-chronic, relapsing inflammatory and ulcerating condition of the functioning reservoir with characteristic clinical, endoscopic and pathological features (Mortensen & Madden, 1993). Definition problems account for the wide spectrum of prevalence rates of pouchitis from different centres and differing response rates to treatment (Shepherd, 1995). Because of the confusion over terminology, some now consider 'chronic relapsing pouchitis' to be a more appropriate appellation for this condition. Symptomatology includes diarrhoea, often bloody, abdominal pain, urgency, discharge, bloating and systemic symptoms: thus the clinical features are not dissimilar to those of the disease for which pouch surgery was performed, ulcerative colitis. Endoscopic examination in pouchitis patients reveals increased vascularity, contact bleeding and ulceration, typical features of active chronic inflammatory bowel disease.

Whilst several conditions cause active inflammation in the reservoir, the pathological hallmarks of pouchitis are acute inflammation and focal ulceration, occurring on a background of marked chronic inflammation and villous atrophy. As one would expect from a chronic ulcerating condition of the small bowel, ulcer-associated cell lineage/pseudopyloric metaplasia is a characteristic marker of the disease (Warren & Shepherd, 1993). The overall histological appearances of pouchitis bear a close likeness to those of ulcerative colitis and are unlike those of Crohn's disease. There is no doubt that histology can predict those patients who are likely to suffer pouchitis. As has been discussed above, it is those patients with 'type C' inflammatory changes (vide supra; Setti Carraro, 1994 & 1998; Veress et al, 1995). The evidence is clear that it is these patients who are most likely to suffer chronic relapsing pouchitis and it is these patients who should be closely surveyed and, perhaps, treated prophylactically to reduce the prevalence of pouchitis.

Once the clinical, endoscopic and histopathological characteristics are present, the diagnosis of pouchitis is effectively established. When so defined the prevalence usually varies between 10% and 20% of patients, although striking variations in prevalence rates continue to characterise the ileal reservoir literature. Whilst there are firmly established links between the adaptive pathological changes in the reservoir and subsequent pouchitis, the literature espouses several different theories as to the cause of pouchitis (Warren & Shepherd, 1993 & 2000). Suggested pathogenetic mechanisms have included stasis, bacterial changes with or without mucolysis, mucosal ischaemia, mucosal prolapse, Crohn's disease, mucosal pathology as a result of a lack of small intestinal nutrients and recurrent ulcerative colitis in a reservoir with colonic phenotypic change. Whilst the theorem that stasis and bacterial changes could cause pouchitis is supported by the relative success of metronidazole, other antibiotics and probiotics in the treatment and prevention of pouchitis (Mimura et al, 2004; Sandborn & Pardi, 2004), it would seem that these are important for the chronic mucosal changes/adaptation but that additional factors are required to produce pouchitis (Warren & Shepherd, 1993).

There are notable associations between an original diagnosis of ulcerative colitis and pouchitis. The most favoured hypothesis for the cause of pouchitis is that it represents a re-emergence of ulcerative colitis in reservoirs with colonic metaplasia/colonic phenotypic change (Warren & Shepherd, 1993; Luukonnen et al, 1994). Most accept that pouchitis is essentially a disease of ulcerative colitis patients and not of FAP patients. There are intriguing associations between ulcerative colitis, extra-intestinal manifestations and pouchitis (especially primary sclerosing cholangitis and arthritis)(Lohmuller et al, 1990; Penna et al, 1996; Hata et al, 2003). Like ulcerative colitis, pouchitis shows a strong negative association with smoking (Merrett et al, 1996). Although there is no evidence of a link between the prevalence of pouchitis and pre-existing backwash ileitis (Gustavsson et al, 1989) or the extent of colitis in the proctocolectomy specimen (Samarasekara et al, 1996), re-emergence of ulcerative colitis in ileal mucosa, which has undergone phenotypic change, remains the most favoured theorem for the pathogenesis of pouchitis (Warren & Shepherd, 1993 & 2000). The most contentious facet of this theorem is the significance and the importance of colonic phenotypic change in the mucosa. As already indicated, current evidence would suggest that 'colonic metaplasia' is not complete in the reservoir: it is this area of reservoir mucosal pathophysiology that demands further research.

3. Can pouch histology predict those at high risk from pouch and cuff neoplasia?
The concept of proctocolectomy is to remove all potentially neoplastic tissue in both ulcerative colitis and FAP patients. Nevertheless the surgery neither removes all colorectal mucosa nor abrogates the neoplastic potential, particularly in FAP, in which adenomas are increasingly seen in the ileal mucosa of the reservoir (Nugent et al, 1993; Thompson-Fawcett et al, 2001). Neoplastic change in the reservoir has been principally demonstrated arising from remaining rectal mucosa (the cuff) at the lower aspect of the reservoir. Colonic phenotypic change in ileal mucosa, in combination with inflammatory change and associated epithelial hyperproliferation, at least suggests the potential for increased neoplastic risk of the ileal mucosa in the reservoir (Shepherd, 1990). In the experience of most groups, dysplasia and carcinoma, in the ileal reservoir mucosa of ulcerative colitis patients, are extremely rare. However, workers from Sweden have intensively studied patients over many years with multiple endoscopies and biopsies and they have demonstrated relatively high rates of dysplasia (in ulcerative colitis patients): in their studies about 10% of reservoir patients develop the most florid inflammatory changes with severe villous atrophy. It is this group that is subject to pouchitis and 71% of patients in this group have had dysplasia including one with high grade dysplasia (Veress et al, 1995; Gullberg et al, 1997).

These studies would suggest that there is potential for neoplastic change within the ileal mucosa of the pelvic ileal reservoir in UC patients. For management purposes, it would seem that the highest risk is with those patients with the most advanced pathological changes, those most likely to develop pouchitis. As this patient group can, seemingly, be identified within six months of ileostomy reversal (Setti Carraro et al, 1994 & 1998), it would seem that these patients should be selected for the most comprehensive surveillance. Management for reservoir mucosal dysplasia should be similar to that for ulcerative colitis.

Currently we should maintain a balanced attitude toward neoplastic risk in the pouch. Dysplasia, in native ileal mucosa, has only been described from one centre and no other centre has yet seen such levels of dysplastic changes. On the other hand there is concern about the pouch in FAP and about the remaining rectal 'cuff' in UC patients. There is now increasing evidence (Ziv et al, 1994; Remzi et al, 2003) of cuff dysplasia but it remains uncertain what the likely progression to cancer is. It is clear that the cuff, as well as those with type C pouch pathology, demand close surveillance (McLeod et al, 2006). Newer endoscopic techniques, especially high-magnification chromoscopic pouchoscopy, may be of considerable value for the surveillance of the pouch and the columnar cuff (Hurlstone et al, 2004).

4. Has histology aided our understanding of diversion disease?
Diversion colitis is an iatrogenic inflammation of the large bowel, induced by diversion of the faecal stream. Colon is most often excluded from the faecal steam during Hartmann's operation for obstruction of the sigmoid colon and/or rectum, most often for carcinoma or complicated diverticular disease. Diversion is performed for varied paediatric conditions, especially Hirschsprung's disease. Inflammatory bowel disease may also be an indication for diversion: in Crohn's disease to ameliorate the disease whilst, in ulcerative colitis, the rectum is defunctioned during the three-stage ileal pouch procedure. Diversion proctocolitis is associated with characteristic macroscopic and histological features. Despite this, symptomatology is very variable. Although pathological changes do occur in the majority of diverted large intestines, by no means all patients suffer symptoms. Rectal bleeding, mucus diarrhoea and abdominal pain are all described but are not consistent features of the disease.

Despite much literature suggesting the opposite, the cause of diversion colitis remains uncertain. Harig et al (1989) first suggested that butyrate, the preferred metabolic substrate for colonic epithelial cells, was deficient in the diverted colon and rectum and that this deficiency was the cause of diversion pathology. In support of their theorem they induced clinical remission of the disease by the instillation of butyrate enemas. Against this evidence is the only controlled trial of butyrate, which has shown no significant improvement, compared to controls (Guillemot et al, 1991). The same group have observed reduction of strict anaerobes in the defunctioned intestine and have suggested that this altered microflora may directly induce inflammation (Neut et al, 1989) whilst, more recently, they have suggested that increased nitrate-reducing bacteria may be a factor in the induction of inflammation (Neut et al, 1997). The exact aetiopathogenesis of inflammation in diversion proctocolitis remains uncertain and further research is needed.

There has been much perplexity over the histological changes seen in diverted large intestine. This is largely because it has only been recently appreciated that the histological features of the disease vary according to the nature of the disease, if any, for which the bowel was diverted (Warren & Shepherd, 1992 & 2000; Edwards et al, 1999). For instance the appearances of the rectum, defunctioned after total colectomy in chronic ulcerative colitis, are very different from those of diverted colon in Crohn's disease (Warren & Shepherd 1992). The most characteristic histological feature of diversion is lymphoid follicular hyperplasia (Yeong et al, 1991). This is apparent endoscopically as the nodularity that is so characteristic of the disease, especially in children. The nodules may show overlying aphthoid ulceration and this should not be taken to represent Crohn's disease (Lusk et al, 1984). The great majority of diverted intestines show mucosal abnormality but the severity and pattern of the disease are very variable and not predictable by the length of time the bowel has been diverted (Komorowski, 1990; Geraghty & Talbot, 1991). Thus there is a histological spectrum from mild chronic inflammation and crypt architectural distortion through to florid active inflammation mimicking active chronic inflammatory bowel disease, especially ulcerative colitis (Komorowski, 1990; Ma et al, 1990; Warren & Shepherd, 2000). Such mimicry is further fuelled by the occasional observation of well-defined epithelioid cell granulomata in the mucosa of diversion colitis (Ma et al, 1990; Warren & Shepherd, 1992). This, alone, should not be taken as evidence of Crohn's disease. The histological changes of diversion are apparent within three months of defunctioning and may be rapidly restored to normality by re-anastomosis (Warren & Shepherd, 2000).

5. Should assessment of a diverted bowel segment provoke a change in the diagnosis of the type of inflammatory bowel disease?
The answer to this is usually 'No'. Diversion, just like pouch pathology, may provoke profound mimicry of other inflammatory conditions, especially Crohn's disease, and it is essential that the evidence for such a change of diagnosis is sought, not in intestine that has been subject to all sorts of new provoking insults and environmental changes, but in 'virginal' pathology, most notably, in the case of the colectomy performed for CIBD, in that colectomy specimen and in pre-existing biopsies. This is particularly so for the proctectomy specimen, removed during the three-stage pouch procedure. Defunctioning the rectum in patients with ulcerative colitis may induce florid inflammatory changes. These may be manifest clinically and endoscopically as a severe active proctitis with nodularity and ulceration, which may be more severe than the original ulcerative colitis affecting the rectum. Histologically, the rectal stump shows the characteristic features of ulcerative colitis together with florid lymphoid hyperplasia (the endoscopic nodularity) and, often, ulceration (frequently overlying hyperplastic lymphoid follicles)(Warren et al, 1993). In addition, fissures, mucosal granulomas and patchiness of inflammation are seen. It is easy to see how these changes may be misconstrued as Crohn's disease by inexperienced observers, especially as transmural inflammation in the form of lymphoid aggregates is also a characteristic feature (Warren et al, 1993). We believe that the confusing histological changes seen in rectal stumps result from a combination of diversion proctitis and pre-existing ulcerative colitis and that the pathological diagnosis of inflammatory bowel disease should be restricted to the macroscopic and microscopic assessment of the colectomy specimen, together with the clinical, radiological and endoscopic assessment of the whole patient (Warren et al, 1993). A diagnosis of Crohn's disease should not be based solely on the histopathological appearances seen in the defunctioned rectum (Warren & Shepherd, 2000).

One curiosity of diversion disease, and indeed of chronic inflammatory bowel disease, is the fact that the pathology (and, usually, the clinical features) of ulcerative colitis frequently worsens in diverting the faecal stream and yet the pathology of Crohn's disease improves when the colon is defunctioned (Edwards et al, 1999). In addition to the changes that may induce mimicry of Crohn's disease, namely transmural inflammation, granulomas and fissures (Warren et al, 1993), the defunctioned rectum in ulcerative colitis shows florid lymphoid follicular hyperplasia, evidence of activity in the form of disruptive crypt abscesses and surface ulceration. A characteristic additional feature is the presence of summit-type lesions with pseudomembrane formation, closely mimicking pseudomembranous colitis (PMC)(Warren et al, 1993). It may be that these features represent a combination of the original inflammatory bowel disease, enhanced by diversion-type pathology, with superimposed mucosal ischaemia to account for the mimicry of PMC.

The rectum is diverted, in ulcerative colitis, to facilitate subsequent pouch surgery, not necessarily in the hope of improving the disease. In Crohn's disease, the colon is diverted with disease amelioration very much in mind. About two-thirds of patients with Crohn's colitis will achieve sustained clinical remission subsequent to diversion, which may also be effective for perianal Crohn's disease that fails to respond to other measures, although occasionally perianal disease may rapidly worsen (Warren & Shepherd, 2000). Reconnection of the faecal steam induces recurrent disease in approximately 40% of those diverted for Crohn's colitis. Systematic pathological review of the diverted colon in Crohn's disease has not been undertaken but some notable observations have been made. Firstly the colon shows considerable reduction in luminal diameter, a feature that may also been seen in diversion of the colon and rectum, performed upon normal bowel or that affected by ulcerative colitis. This involution may provide difficulties for the surgeon attempting re-anastomosis. Histologically there is reduction in ulceration and both acute and chronic inflammation. Granulomas are usually regarded as transient features in Crohn's disease and this has been used to explain why Crohn's granulomas do not often contain such calcified bodies (unlike in sarcoidosis in which the granulomas are thought to represent a long-standing characteristic). A distinctive feature of diverted Crohn's colitis is the presence of granulomas containing calcified Schaumann bodies (Warren & Shepherd, 2000).

Should Crohn's colitis relapse after re-anastomosis subsequent to a period of diversion, often the only course of action is total proctocolectomy. The interpretation of the histopathology of such a resected specimen also requires caution. Partial resolution of the Crohn's colitis with the superimposed histological changes of diversion colitis may produce pathology indistinguishable from ulcerative colitis. The danger here is that the preceding clinicopathological and radiological evidence for Crohn's colitis may be overlooked. Fortunately in most cases adequate provision of blocks for histological examination will reveal transmural inflammation in the form of lymphoid aggregates or evidence of granulomatosis, particularly deep within the wall. The isolated histopathological reporting of the resected colon following diversion and reconnection can result in an erroneous diagnosis, as surely as the isolated reporting of the defunctioned rectum in ulcerative colitis. This author strongly recommends that all resections and biopsies are reviewed before a change of diagnosis is contemplated in patients with inflammatory bowel disease who have undergone these forms of surgery.

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